A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin.
Cell Rep
; 22(8): 2006-2015, 2018 02 20.
Article
en En
| MEDLINE
| ID: mdl-29466729
ABSTRACT
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by a truncated lamin A protein (progerin) that drives cellular and organismal decline. HGPS patient-derived fibroblasts accumulate genomic instability, but its underlying mechanisms and contribution to disease remain poorly understood. Here, we show that progerin-induced replication stress (RS) drives genomic instability by eliciting replication fork (RF) stalling and nuclease-mediated degradation. Rampant RS is accompanied by upregulation of the cGAS/STING cytosolic DNA sensing pathway and activation of a robust STAT1-regulated interferon (IFN)-like response. Reducing RS and the IFN-like response, especially with calcitriol, improves the fitness of progeria cells and increases the efficiency of cellular reprogramming. Importantly, other compounds that improve HGPS phenotypes reduce RS and the IFN-like response. Our study reveals mechanisms underlying progerin toxicity, including RS-induced genomic instability and activation of IFN-like responses, and their relevance for cellular decline in HGPS.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Estrés Fisiológico
/
Interferones
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Lamina Tipo A
/
Replicación del ADN
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Rep
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos